Benzylidene derivatives represented by the following general formula III ##STR4## wherein R.sup.1 and R.sup.2 each independently is lower alkyl, lower alkoxy or halogen; Y is SO.sub.2, SO or CO; --A-- is optionally substituted lower alkylene; --B-- is --CH.sub.2 -- or --O--; or --A-- and --B-- taken together may form optionally substituted phenylene or optionally substituted lower alkenylene; and R is hydrogen, optionally substituted lower alkyl, cycloalkyl, lower alkoxy, hydroxy, optionally substituted aryl, optionally substituted arylalkyl; optionally substituted arylalkyloxy, heterocyclic ring or N-protecting group are known to include many pharmaceutically useful compounds. For example, it has been suggested that a compound of the formula III wherein --A-- is --CH.sub.2 CH.sub.2 --, --B-- is --O--, Y is CO, R is --CH.sub.3, and R.sup.1 and R.sup.2 are both t-butyl can be useful as an anti-inflammatory agent with low ulcerogenic potential. Sung J. L. et al., Drugs of the Future 17(1): 12-14 (1992); and S. Wong et al., Agents Actions 37: 90-98 (1992). It has also been found that a kind of benzylidene derivatives of the formula III have an ability to suppress the production of PGE.sub.2, LTB.sub.4 and IL-1 in vitro and prevent edema with little damages of gastric mucosa in vivo, and can be excellent non-steroidal anti-inflammatory agents. These are disclosed in EP Appln. No. 93308369.3 (Publication No. 595546) corresponding to U.S. patent application Ser. No. 08/142,146.
These benzylidene derivatives of the formula III can be prepared in a conventional manner, for example, according to the following reaction scheme. ##STR5## In the reaction scheme above, R is a as defined above and R.sup.3 is hydroxy-protecting group in EP patent application No. 93308369.3 (Publication No. 595546) corresponding to U.S. patent application No. 08/142,146. Thus, hydroxy-protected 3,5-di-tert-butyl-4-hydroxybenzaldehyde 4 is reacted with .gamma.-sultam derivative 2 under a conditions for aldol reaction to obtain an aldol addition compound 5. The compound 1, when deprotected and dehydrated in the presence of an acid, gives the objective benzylidene derivative 3' as a mixture of stereoisomers in (E)- and (Z) forms, which is then subjected to resolution, when a given isomer is desired. For example, a compound of the formula 3' wherein R is --CH.sub.3 (5-(3,5-di-tert-butyl-4-hydroxybenzylidene)-2-methyl-1,2-isothiazolidine-1 ,1-dioxide), when tested to evaluate inhibitory activity against the production of PGE.sub.2 in rat synovial membrane cells, against the production of LTB.sub.4 in rat celiac cells, or against the production of IL-1 under LPS stimulation in THP-1 cells, showed different activities as follows.
______________________________________ PGE.sub.2 LTB.sub.4 L-1 (Rat SVC) (Rat PEC) (THP-1) IC.sub.50 (.mu.M) ______________________________________ (E) &lt;0.001 2.8 21 (Z) &lt;0.001 1.8 29 ______________________________________
The separation of isomers of compounds shown by the formula III, however, is difficult and requires troublesome procedures, which prevented the industrial production of objective benzylidene derivatives. Therefore, a novel method for producing compounds III, especially an isomer thereof, which is stereoselective and applicable to industrial process, is needed to promote the development of medicinal drugs such as non-steroidal anti-inflammatory agents.